Dysregulation of endocannabinoid concentrations in human subcutaneous adipose tissue in obesity and modulation by omega-3 polyunsaturated fatty acids.

Obesity is believed to be associated with a dysregulated endocannabinoid system which may reflect enhanced inflammation. However, reports of this in human white adipose tissue (WAT) are limited and inconclusive. Marine long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) have anti-inflammatory actions and therefore may improve obesity-associated adipose tissue inflammation. Therefore, fatty acid (FA) concentrations, endocannabinoid concentrations, and gene expression were assessed in subcutaneous WAT (scWAT) biopsies from healthy normal weight individuals (BMI 18.5-25 kg/m2) and individuals living with metabolically healthy obesity (BMI 30-40 kg/m2) prior to and following a 12-week intervention with 3 g fish oil/day (1.1 g eicosapentaenoic acid (EPA) + 0.8 g DHA) or 3 g corn oil/day (placebo). WAT from individuals living with metabolically healthy obesity had higher n-6 PUFAs and EPA, higher concentrations of two endocannabinoids (anandamide (AEA) and eicosapentaenoyl ethanolamide (EPEA)), higher expression of phospholipase A2 Group IID (PLA2G2D) and phospholipase A2 Group IVA (PLA2G4A), and lower expression of CNR1. In response to fish oil intervention, WAT EPA increased to a similar extent in both BMI groups, and WAT DHA increased by a greater extent in normal weight individuals. WAT EPEA and docosahexaenoyl ethanolamide (DHEA) increased in normal weight individuals only and WAT 2-arachidonyl glycerol (2-AG) decreased in individuals living with metabolically healthy obesity only. Altered WAT fatty acid, endocannabinoid, and gene expression profiles in metabolically healthy obesity at baseline may be linked. WAT incorporates n-3 PUFAs when their intake is increased which affects the endocannabinoid system; however, effects appear greater in normal weight individuals than in those living with metabolically healthy obesity.

In infants with sufficient vitamin D status at birth, vitamin D supplementation does not impact immune development.

BACKGROUND: Low vitamin D levels have been associated with allergic diseases. Vitamin D has potent immunomodulatory properties, but the mechanisms remain unclear. We have investigated the effect of oral vitamin D supplementation on circulating immune cell phenotypes in infants. METHOD: A double-blinded randomised controlled trial was conducted to investigate the effect of oral vitamin D supplementation (400 IU/d) on eczema and immune development. A subset of 78 infants was included in this analysis. Phenotypic analysis of immune cell subsets was performed using flow cytometry. RESULTS: Vitamin D supplementation resulted in median 25(OH)D levels of 80.5 vs 59.5 nmol/L in the placebo group at 3 months of age (P = .002) and 87.5 vs 77 nmol/L at 6 months of age (P = .08). We observed significant changes in immune cell composition from birth (cord blood) to 6 months of age. Vitamin D supplementation did not impact these changes, nor did immune cell composition correlate with plasma 25(OH)D levels. Through exploratory analysis, we identified possible associations with eczema development and increased abundance of naïve CD4- T cells at birth, as well as associations with basophils, iNKT and central memory CD4+ T cells, and altered expression patterns of IgE receptor (FcεR1) on monocytes and dendritic cells with eczema at 6 months. CONCLUSIONS: Vitamin D supplementation in infants who were vitamin D sufficient at birth did not affect developmental changes in immune cells during the first 6 months of life. However, immune cell profiles at birth and at 6 months of age were associated with early life eczema.

Direct infant UV light exposure is associated with eczema and immune development.

BACKGROUND: Suboptimal vitamin D levels during critical periods of immune development have emerged as an explanation for higher rates of allergic diseases associated with industrialization and residing at higher latitudes. OBJECTIVE: We sought to determine the effects of early postnatal vitamin D supplementation on infant eczema and immune development. METHODS: By using a double-blind randomized controlled trial, newborn infants were randomized to receive vitamin D supplementation (400 IU/d) or a placebo until 6 months of age. Some infants also wore personal UV dosimeters to measure direct UV light (290-380 nm) exposure. Infant vitamin D levels were measured at 3 and 6 months of age. Eczema, wheeze, and immune function outcomes were assessed at 6 months of age. RESULTS: At 3 (P < .01) and 6 (P = .02) months of age, vitamin D levels were greater for the vitamin D-supplemented group than the placebo group, but there was no difference in eczema incidence between groups. Infants with eczema were found to have had less UV light exposure (median, 555 Joules per square meter [J/m2; interquartile range, 322-1210 J/m2]) compared with those without eczema (median, 998 J/m2 [interquartile range, 676-1577 J/m2]; P = .02). UV light exposure was also inversely correlated with IL-2, GM-CSF, and eotaxin production to Toll-like receptor ligands. CONCLUSION: This study is the first to demonstrate an association between greater direct UV light exposures in early infancy with lower incidence of eczema and proinflammatory immune markers by 6 months of age. Our findings indicate that UV light exposure appears more beneficial than vitamin D supplementation as an allergy prevention strategy in early life.

Under-utilisation of ß-blockers in patients with acute coronary syndrome and comorbid chronic obstructive pulmonary disease.

BACKGROUND: ß-blockers are an established mainstay of therapy in acute coronary syndrome (ACS). Despite substantial evidence of their safety and efficacy in chronic obstructive pulmonary disease (COPD) patients, their use in this population remains limited internationally, likely due to fears of inducing bronchospasm. In Australia, little is known about the use of ß-blockers in COPD patients hospitalised for ACS. AIM: To determine if ß-blockers are under-prescribed at discharge for patients with COPD hospitalised for ACS compared to patients without a diagnosis of COPD. METHODS: Retrospective analysis of a tertiary metropolitan hospital computer database was undertaken to identify the first 250 patients hospitalised with ACS from 1 March 2015. RESULTS: Of the 250 patients analysed, there were five in-hospital fatalities, leaving 245 patients for final analysis. Patients with ACS and COPD received fewer ß-blockers at discharge than those with ACS alone (66.7% vs 86.2%, P < 0.05). After controlling for clinically meaningful confounding factors, a logistic regression analysis model determined that, for patients with ACS, the presence of COPD was the only significant predictor of receiving a ß-blocker at discharge. CONCLUSION: Despite strong evidence supporting the use of ß-blockers in COPD patients with ACS, Australian patients with COPD remain under-treated for ACS. More work is needed to alter prescribing attitudes.

Effect of salmon consumption during pregnancy on maternal and infant faecal microbiota, secretory IgA and calprotectin.

The gut microbiota plays an important role in the development of the immune and gastrointestinal systems of infants. In the present study, we investigated whether increased salmon consumption during pregnancy, maternal weight gain during pregnancy or mode of infant feeding alter the markers of gut immune defence and inflammation. Women (n 123) who rarely ate oily fish were randomly assigned to continue consuming their habitual diet or to consume two 150 g portions of farmed salmon per week from 20 weeks of pregnancy to delivery. Faecal samples were collected from the mothers (n 75) at 38 weeks of gestation and from their infants (n 38) on days 7, 14, 28 and 84 post-partum. Fluorescence in situ hybridisation was used to determine faecal microbiota composition and ELISA to measure faecal secretory IgA (sIgA) and calprotectin concentrations. There was no effect of salmon consumption on maternal faecal microbiota or on maternal or infant faecal sIgA and calprotectin concentrations. The degree of weight gain influenced maternal faecal microbiota, and the mode of infant feeding influenced infant faecal microbiota. Faecal samples collected from infants in the salmon group tended to have lower bacterial counts of the Atopobium cluster compared with those collected from infants in the control group (P=0·097). This difference was significant in the formula-fed infants (P< 0·05), but not in the exclusively breast-fed infants. In conclusion, the impact of oily fish consumption during pregnancy on maternal and infant gut microbiota composition is limited, but significant differences are associated with maternal weight gain during pregnancy and mode of infant feeding.

Short-term infusion of a fish oil-based lipid emulsion modulates fatty acid status, but not immune function or (anti)oxidant balance: a randomized cross-over study.

BACKGROUND AND AIMS: Studies suggest clinical benefits of parenteral fish oil (FO), rich in n-3 polyunsaturated fatty acids (PUFAs), over soyabean oil (SO), rich in n-6 PUFAs, in patients with pro-inflammatory conditions such as sepsis and trauma. Because the mechanisms behind these observations remain unclear, the present study explored the effects of intravenous infusion of FO and SO on fatty acid incorporation, immune functions and (anti)oxidant balance in healthy human volunteers. METHODS: Saline, a SO emulsion and a FO emulsion were administered for one hour on three consecutive days at a rate of 0·2 g/kg BW/h to eight subjects in a randomized cross-over design with a 3-week interval between treatments. Plasma phospholipid and peripheral blood mononuclear cell (PBMC) fatty acid compositions, and leucocyte counts and functions were assessed prior to the first infusion (T = 0, baseline) and 1 day (T = 4, early effects) and 8 days (T = 11, late effects) after the third infusion. RESULTS: Fish oil infusion significantly increased n-3 PUFA proportions and decreased n-6 PUFA proportions in plasma phospholipids and PBMCs. There were no differences in immune functions or (anti)oxidant balance between treatments at any time. CONCLUSIONS: The present lipid infusion protocol appears to be safe and well tolerated and provides significant incorporation of n-3 PUFAs into plasma phospholipids and PBMCs. In the absence of overt inflammation, no direct effects of FO were observed on immune function or (anti)oxidant balance. This model may be useful to evaluate effects of parenteral lipids in other settings, for example in individuals displaying an inflammatory state.

Plasma inflammatory and vascular homeostasis biomarkers increase during human pregnancy but are not affected by oily fish intake.

The Salmon in Pregnancy Study investigated whether the increased consumption of (n-3) long-chain PUFA (LC-PUFA) from farmed Atlantic salmon affects immune function during pregnancy and atopic disease in neonates compared with a habitual diet low in oily fish. In this context, because the ingestion of (n-3) LC-PUFA may lower the concentrations of inflammatory biomarkers, we investigated whether the consumption of oily fish affects the levels of inflammatory cytokines and vascular adhesion factors during pregnancy. Pregnant women (n = 123) were randomly assigned to continue their habitual diet (control group, n = 61), which was low in oily fish, or to consume two 150-g salmon portions/wk (salmon group, n = 62; providing 3.45 g EPA plus DHA) from 20 wk of gestation until delivery. Plasma inflammatory cytokines and vascular adhesion factors were measured in maternal plasma samples. Inflammatory biomarkers, including IL-8, hepatocyte growth factor, and monocyte chemotactic protein, increased over the course of pregnancy (P < 0.001), whereas plasma matrix metalloproteinase 9, IL-6, TNFα, and nerve growth factor concentrations were not affected. Vascular homeostasis biomarkers soluble E-selectin, soluble vascular adhesion molecule-1, soluble intercellular adhesion molecule (sICAM)-1, and total plasminogen activator inhibitor-1 increased as pregnancy progressed (P < 0.001). The plasma sICAM-1 concentration was greater in the control group than in the salmon group at wk 20 (baseline) and 38 (P = 0.007) but there was no group x time interaction, and when baseline concentration was used as a covariate, the groups did not differ (P = 0.69). The remaining biomarkers analyzed were similar in both groups. Therefore, although some inflammatory and vascular homeostasis biomarkers change during pregnancy, they are not affected by the increased intake of farmed salmon.

Salmon consumption during pregnancy alters fatty acid composition and secretory IgA concentration in human breast milk.

Fish oil supplementation during pregnancy alters breast milk composition, but there is little information about the impact of oily fish consumption. We determined whether increased salmon consumption during pregnancy alters breast milk fatty acid composition and immune factors. Women (n = 123) who rarely ate oily fish were randomly assigned to consume their habitual diet or to consume 2 portions of farmed salmon per week from 20 wk of pregnancy until delivery. The salmon provided 3.45 g long-chain (LC) (n-3) PUFA/wk. Breast milk fatty acid composition and immune factors [soluble CD14, transforming growth factor-ß (TGFß)1, TGFß2, and secretory IgA] were analyzed at 1, 5, 14, and 28 d postpartum (PP). Breast milk from the salmon group had higher proportions of EPA (80%), docosapentaenoic acid (30%), and DHA (90%) on d 5 PP compared with controls (P < 0.01). The LC (n-6) PUFA:LC (n-3) PUFA ratio was lower for the salmon group on all days of PP sampling (P ≤ 0.004), although individual (n-6) PUFA proportions, including arachidonic acid, did not differ. All breast milk immune factors decreased between d 1 and 28 PP (P < 0.001). Breast milk secretory IgA (sIgA) was lower in the salmon group (d 1-28 PP; P = 0.006). Salmon consumption during pregnancy, at the current recommended intakes, increases the LC (n-3) PUFA concentration of breast milk in early lactation, thus improving the supply of these important fatty acids to the breast-fed neonate. The consequence of the lower breast milk concentration of sIgA in the salmon group is not clear.

ß2-1 Fructans have a bifidogenic effect in healthy middle-aged human subjects but do not alter immune responses examined in the absence of an in vivo immune challenge: results from a randomised controlled trial.

ß2-1 fructans are considered to be prebiotics. Current literature indicates that ß2-1 fructans may modulate some aspects of immune function, improve the host's ability to respond to certain intestinal infections, and modify some inflammatory outcomes in human subjects. However, there is a need to find out more about the modulation of immune markers by ß2-1 fructans in humans. Healthy human subjects aged 45-65 years were randomly allocated to ß2-1 fructans (Orafti® Synergy1; 8 g/d; n 22) or the digestible carbohydrate maltodextrin as placebo (n 21) for 4 weeks. Blood, saliva and faecal samples were collected at study entry and after 4 weeks. Immune parameters were measured using the blood and saliva samples and bifidobacteria were measured in the faecal samples. Faecal bifidobacteria numbers increased in the Orafti® Synergy1 group (P < 0·001) and were different at 4 weeks from numbers in the placebo group (P = 0·001). There was no significant effect of Orafti® Synergy1 on any of the immune parameters measured (blood immune cell subsets, total serum Ig, salivary IgA, neutrophil and monocyte phagocytosis of Escherichia coli and respiratory burst in response to E. coli or phorbol ester, natural killer cell activity, T cell activation and proliferation, production of six cytokines by T cells). It is concluded that, compared with maltodextrin, Orafti® Synergy1 has a bifidogenic effect in healthy middle-aged human subjects but does not alter immune responses examined in the absence of an in vivo immune challenge.

Documentation of functional and clinical effects of infant nutrition: setting the scene for COMMENT.

The Early Nutrition Academy and the Child Health Foundation, in collaboration with the Committee on Nutrition, European Society for Paediatric Gastroenterology, Hepatology and Nutrition, held a workshop in March 2011 to explore guidance on acquiring evidence on the effects of nutritional interventions in infants and young children. The four objectives were to (1) provide guidance on the quality and quantity of evidence needed to justify conclusions on functional and clinical effects of nutrition in infants and young children aged <3 years; (2) agree on a range of outcome measures relevant to nutrition trials in this age group for which agreed criteria are needed; (3) agree on an updated 'core data set' that should generally be recorded in nutrition trials in infants and young children, and (4) provide guidance on the use of surrogate markers in paediatric nutrition research. The participants discussed these objectives and agreed to set up six first working groups under the auspices of the Consensus Group on Outcome Measures Made in Paediatric Enteral Nutrition Clinical Trials (COMMENT). Five groups will aim to identify and define criteria for assessing key outcomes, i.e. growth, acute diarrhoea, atopic dermatitis and cows' milk protein allergy, infections and 'gut comfort'. The sixth group will review and update the 'core data set'. The COMMENT Steering Committee will discuss and decide upon a method for reaching consensus which will be used by all working groups and plan to meet again within 2 years and to report and publish their conclusions.

Dysregulation of Subcutaneous White Adipose Tissue Inflammatory Environment Modelling in Non-Insulin Resistant Obesity and Responses to Omega-3 Fatty Acids - A Double Blind, Randomised Clinical Trial.

Background: Obesity is associated with enhanced lipid accumulation and the expansion of adipose tissue accompanied by hypoxia and inflammatory signalling. Investigation in human subcutaneous white adipose tissue (scWAT) in people living with obesity in which metabolic complications such as insulin resistance are yet to manifest is limited, and the mechanisms by which these processes are dysregulated are not well elucidated. Long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) have been shown to modulate the expression of genes associated with lipid accumulation and collagen deposition and reduce the number of inflammatory macrophages in adipose tissue from individuals with insulin resistance. Therefore, these lipids may have positive actions on obesity associated scWAT hypertrophy and inflammation. Methods: To evaluate obesity-associated tissue remodelling and responses to LC n-3 PUFAs, abdominal scWAT biopsies were collected from normal weight individuals and those living with obesity prior to and following 12-week intervention with marine LC n-3 PUFAs (1.1 g EPA + 0.8 g DHA daily). RNA sequencing, qRT-PCR, and histochemical staining were used to assess remodelling- and inflammatory-associated gene expression, tissue morphology and macrophage infiltration. Results: Obesity was associated with scWAT hypertrophy (P < 0.001), hypoxia, remodelling, and inflammatory macrophage infiltration (P = 0.023). Furthermore, we highlight the novel dysregulation of Wnt signalling in scWAT in non-insulin resistant obesity. LC n-3 PUFAs beneficially modulated the scWAT environment through downregulating the expression of genes associated with inflammatory and remodelling pathways (P <0.001), but there were altered outcomes in individuals living with obesity in comparison to normal weight individuals. Conclusion: Our data identify dysregulation of Wnt signalling, hypoxia, and hypertrophy, and enhanced macrophage infiltration in scWAT in non-insulin resistant obesity. LC n-3 PUFAs modulate some of these processes, especially in normal weight individuals which may be preventative and limit the development of restrictive and inflammatory scWAT in the development of obesity. We conclude that a higher dose or longer duration of LC n-3 PUFA intervention may be needed to reduce obesity-associated scWAT inflammation and promote tissue homeostasis. Clinical Trial Registration: www.isrctn.com, identifier ISRCTN96712688.

Modification of subcutaneous white adipose tissue inflammation by omega-3 fatty acids is limited in human obesity-a double blind, randomised clinical trial.

BACKGROUND: Obesity is associated with enhanced inflammation. However, investigation in human subcutaneous white adipose tissue (scWAT) is limited and the mechanisms by which inflammation occurs have not been well elucidated. Marine long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) have anti-inflammatory actions and may reduce scWAT inflammation. METHODS: Subcutaneous white adipose tissue (scWAT) biopsies were collected from individuals living with obesity (n=45) and normal weight individuals (n=39) prior to and following a 12-week intervention with either 3 g/day of a fish oil concentrate (providing 1.1 g eicosapentaenoic acid (EPA) + 0.8 g docosahexaenoic acid (DHA)) or 3 g/day of corn oil. ScWAT fatty acid, oxylipin, and transcriptome profiles were assessed by gas chromatography, ultra-pure liquid chromatography tandem mass spectrometry, RNA sequencing and qRT-PCR, respectively. FINDINGS: Obesity was associated with greater scWAT inflammation demonstrated by lower concentrations of specialised pro-resolving mediators (SPMs) and hydroxy-DHA metabolites and an altered transcriptome with differential expression of genes involved in LC n-3 PUFA activation, oxylipin synthesis, inflammation, and immune response. Intervention with LC n-3 PUFAs increased their respective metabolites including the SPM precursor 14-hydroxy-DHA in normal weight individuals and decreased arachidonic acid derived metabolites and expression of genes involved in immune and inflammatory response with a greater effect in normal weight individuals. INTERPRETATION: Downregulated expression of genes responsible for fatty acid activation and metabolism may contribute to an inflammatory oxylipin profile and limit the effects of LC n-3 PUFAs in obesity. There may be a need for personalised LC n-3 PUFA supplementation based on obesity status. FUNDING: European Commission Seventh Framework Programme (Grant Number 244995) and Czech Academy of Sciences (Lumina quaeruntur LQ200111901).

Children with egg allergy have evidence of reduced neonatal CD4(+)CD25(+)CD127(lo/-) regulatory T cell function.

BACKGROUND: The role of regulatory T (Treg) cells in allergic predisposition is not known. OBJECTIVE: This study compared the frequency and function of cord blood Treg cells from nonallergic children (n = 18) with those from children who have egg allergy (n = 15) in the first year of life. METHODS: CD4(+) effector T cells and autologous antigen-presenting cells isolated from cord blood mononuclear cells were cocultured with or without CD4(+)CD25(+)CD127(lo/-) Treg cells, and cytokine responses to staphylococcal endotoxin B were assessed after 48 hours. RESULTS: The addition of Treg cell populations to cord blood mononuclear cell cultures resulted in significant reduction in IL-10 (P = .002), IL-13 (P = .012), and IFN-gamma (P < .001) production. Consistent with other reports, effector CD4(+) T-cell responses (IFN-gamma and IL-13) tended to be lower in the allergic group. These neonates showed less significant Treg cell-associated suppression of IFN-gamma (P = .015) compared with that seen in the nonallergic group (P = .001). The allergic group was also less likely (44%) to show Treg cell-associated suppression of IFN-gamma effector responses compared with that seen in the nonallergic group (78%, P = .015). The magnitude of suppression (change in IFN-gamma level when CD4(+)CD25(+)CD127(lo/-) Treg cells were added to responding effector T-cell cultures) was significantly lower in the allergic group (P = .004). There were no between-group differences in the circulating CD4(+)CD25(+)CD127(lo/-) Treg cells (as a percentage of cord blood T cells) or in the FOXP3 expression of these cells. CONCLUSION: This study confirms the presence and activity of Treg cells in cord blood and provides preliminary evidence of differences in neonates who progress to allergic disease in the first year of life.

Presymptomatic differences in Toll-like receptor function in infants who have allergy.

BACKGROUND: Microbial exposure might play a key role in allergy development, but little is known about the role of Toll-like receptors (TLRs). OBJECTIVE: This study explored the association between neonatal TLR microbial recognition/function, allergy risk (maternal allergy), and prospective allergy development. METHODS: Cord blood mononuclear cells (n = 111) were cultured either alone or with optimal concentrations of TLR ligands: lipoteichoic acid (TLR2), polyinosinicpolycytidylic acid (TLR3), LPS with IFN-gamma (TLR4), flagellin (TLR5), imiquimod R837 (TLR7), or CpG (TLR9). Cytokine responses were assessed in relation to allergy risk (maternal allergy) and allergy outcomes (sensitization, food allergy, and atopic dermatitis) at 12 months of age. RESULTS: Maternal allergy (n = 59) was associated with significantly higher neonatal IL-12 and IFN-gamma responses to TLR2, TLR3, and TLR4 activation, whereas TNF-alpha and IL-6 responses to TLR2, TLR4, and TLR5 activation were significantly higher in newborns who subsequently had allergic disease (n = 32). Notably, consistent with previous reports, newborns who had disease had lower T(H)1 IFN-gamma response to mitogens (PHA). CONCLUSION: Allergic disease was associated with increased (rather than decreased) perinatal TLR responses. Further studies are needed to determine how these responses track in the postnatal period and whether this relative hyperresponsiveness is a product of intrauterine influences, including maternal atopy, functional genetic polymorphisms, or both.

Reviewing the preclinical curriculum in a Problem Based Learning driven medical program: challenges and strategies.

This article was migrated. The article was marked as recommended. In order for medical curricula to remain progressive and contemporary, continuous review is critical to ensure that the learners are directed to achieve the intended goals and become workforce ready. We developed a framework for continuous curriculum review at the School of Medicine Fremantle (The University of Notre Dame Australia), taking the key aspects of a curriculum review process into consideration. In planning and implementing the review process we identified several challenges, including management of metadata, work load on staff members, and evaluation. These challenges were addressed successfully by applying necessary strategies using limited resources. The framework we have developed provides a guide to key stakeholders who are involved in medical curriculum review and development.

Maternal smoking in pregnancy: do the effects on innate (toll-like receptor) function have implications for subsequent allergic disease?

: Subtle increases in immaturity of immune function in early infancy have been implicated in the rising susceptibility to allergic disease, particularly relative impairment of type 1 interferon (IFN)-gamma responses in the neonatal period. Although genetic predisposition is a clear risk factor, the escalating rates of allergic disease in infancy suggest that environmental factors are also implicated. We previously showed that maternal smoking in pregnancy may impair neonatal IFN-gamma responses. Our more recent studies now indicate that this common avoidable toxic exposure is also associated with attenuation of innate immune function, with attenuated Toll-like receptor (TLR)-mediated microbial responses (including TLR-2, -3, -4, and -9 responses). Most notably, the effects were more marked if the mothers were also allergic. In this review, we discuss the significance of these observations in the context of the emerging hypothesis that variations in TLR function in early life may be implicated in allergic propensity. There is now growing evidence that many of the key pathways involved in subsequent T-cell programming and regulation (namely, antigen-presenting cells and regulatory T cells) rely heavily on microbe-driven TLR activation for maturation and function. Factors that influence the function and activity of these innate pathways in early life may contribute to the increasing predisposition for allergic disease. Although "cleaner" environments have been implicated, here we explore the possibility that other common environmental exposures (such as maternal smoking) could also play a role.

Yeast-derived ß-1,3/1,6 glucan, upper respiratory tract infection and innate immunity in older adults.

OBJECTIVE: The aims of this study were to test whether yeast-derived ß-1,3/1,6 glucan can prevent the occurrence or reduce the severity of upper respiratory tract infection (URTI) and modulate innate immune responses during winter months in community-dwelling older adults. METHODS: This was a double-blind placebo-controlled trial of community-dwelling adults ages 50 to 70 y randomized to once-daily ß-1,3/1,6 glucan (Wellmune 250 mg/d; n = 50) or identical placebo capsule (n = 50) over 90 d during winter. URTI episodes were medically confirmed. Symptom severity was recorded via self-reported daily Wisconsin Upper Respiratory Tract Infection Score 21. Blood and saliva samples were collected at days 0, 45, and 90 for measurements of innate immune parameters. RESULTS: Forty-nine participants completed the trial in each group. Supplementation was well tolerated. Forty-five URTIs were confirmed: 28 in the placebo group and 17 in the Wellmune group (odds ratio, 0.55; 95% confidence interval, 0.24-1.26; P = 0.149). There was a strong trend for Wellmune to decrease the number of symptom days (P = 0.067). Symptom severity did not differ significantly between groups. Compared with the placebo group, lipopolysaccharide-stimulated blood from participants in the Wellmune group showed an increase in interferon-γ concentration from baseline at day 45 (P = 0.016) and smaller decreases in monokine induced by interferon-γ concentration from baseline at days 45 and 90 (P = 0.032 and 0.046, respectively). No difference was seen in serum or nonstimulated blood cytokines and chemokines or in salivary immunoglobulin A. CONCLUSION: Daily oral ß-1,3/1,6 glucan may protect against URTIs and reduce the duration of URTI symptoms in older individuals once infected. This may be linked to effects on innate immune function. Larger studies are needed to confirm the benefits of ß-1,3/1,6 glucan on URTIs in this older population.

Infective respiratory syncytial virus is present in human cord blood samples and most prevalent during winter months.

BACKGROUND: Human respiratory syncytial virus (RSV) remains the most common cause of severe lower respiratory tract disease amongst infants, and continues to cause annual epidemics of respiratory disease every winter worldwide. Demonstrating placental transmission of viable RSV in human samples is a major paradigm shift in respiratory routes considered likely for RSV transmission. METHODS: Droplet digital PCR (ddPCR) was used to identify RSV present in cord blood mononucleocytes (CBM). CBMs testing positive for RSV were treated with phytohemagglutinin (PHA), PHA and nitric oxide (NO) or PHA, NO and palivizumab, and co-cultured with HeLa cell monolayers. Subsequent immuno-staining for RSV was used to visualize infective viral plaques. RESULTS: RSV was detected in 26 of 45 samples (57.7%) by ddPCR. CBM's collected in winter were more likely to test positive for RSV (17/21 samples, risk = 80%, OR = 7.08; 95% CI 1.80-27.80; p = 0.005) compared to non-winter months (9/24 samples, 37.5%). RSV plaques were observed in non-treated and treated co-cultured HeLa monolayers. CONCLUSIONS: Demonstrating active RSV in CBMs suggests in utero transmission of infective virus to the fetus without causing overt disease. This is likely to have an important impact on immune development as well as future virus-host interactions, thereby warranting further investigation.

Fatty acid status and antioxidant defense system in mothers and their newborns after salmon intake during late pregnancy.

OBJECTIVE: The aim of the present study was to assess the maternal and newborn status of erythrocyte fatty acids and the antioxidant defense system after the intake of two portions of salmon per week during late pregnancy. METHODS: Pregnant women (N = 123) were randomly assigned to continue their habitual diet, which was low in oily fish (control group, n = 61) or to consume two 150-g salmon portions per week (salmon group, n = 62) beginning at 20 wk of gestation and lasting until delivery. Fatty acids, selenium, and glutathione concentrations and antioxidant defense enzyme activities were measured in maternal erythrocytes at 20, 34, and 38 wk of pregnancy, and in cord erythrocytes collected at birth. Plasma concentrations of antioxidant molecules were measured. RESULTS: Compared with the control group, consuming salmon had little effect on erythrocyte fatty acids in either mothers or newborns. Components of the antioxidant defense system did not differ between groups. Glutathione peroxidase activity and the concentrations of tocopherols, retinol, and coenzyme Q10 were significantly lower in cord blood compared with maternal blood at week 38 in both groups. CONCLUSION: Maternal and newborn erythrocyte fatty acids are not strongly affected by the intake of two portions of salmon per week during the second half of pregnancy, although erythrocyte docosahexaenoic acid might be increased in newborns. Maternal and newborn antioxidant defense systems are not impaired by intake of salmon from 20 wk gestation.

Evidence for Involvement of IL-9 and IL-22 in Cows' Milk Allergy in Infants.

Although allergic inflammation is characterized by a T helper (Th) 2-dominant immune response, the discovery of a role for new T cell subsets in inflammatory diseases has added an additional layer of complexity to the understanding of the pathogeneses of allergic diseases. We evaluated plasma cytokine profiles in infants with cows' milk allergy (CMA), who were being treated with an elimination diet. In a prospective, randomized and controlled study, infants (aged 8.4 ± 3.9 months) with CMA were treated with an elimination diet for 120 days, which replaced cows' milk with a hydrolysed soy protein formula (n = 26) or a free amino acid formula (n = 20). Blood samples were collected before treatment during active disease (T0) and after 120 days, when symptoms were absent (T1). Plasma cytokine concentrations were measured. Infants with CMA had higher plasma concentrations of interleukin (IL)-4 and IL-13 and lower concentrations of IL-9, IL-17A and interferon-γ, compared with healthy breast-fed infants. At T0, there was a positive correlation between blood eosinophil numbers and plasma concentrations of IL-4, IL-9, IL-17A and IL-22. Treatment with a cows' milk elimination diet resulted in a decrease in plasma IL-4, IL-9, IL-13 and IL-22 and an increase in plasma IL-17A. We conclude that IL-4 and IL-13 are elevated in active CMA. The association of IL-9 and IL-22 with eosinophilia, and the decrease in these two cytokines with cows' milk elimination, suggests that they both play a role in the symptoms observed in CMA and may be important targets for future interventions.